Coated stent

ABSTRACT

Stents with coatings comprising a combination of a restenosis inhibitor comprising an HMG-CoA reductase inhibitor and a carrier. Also provided are methods of coating stents with a combination of an HMG-CoA reductase inhibitor and a carrier. A preferred example of a restenosis inhibitor is cerivastatin. The stent coatings have been shown to release restenosis inhibitors in their active forms.

This application is a continuation of application Ser. No. 09/991,235,filed Oct. 22, 2001, now abandoned which application is incorporatedherein by reference.

BACKGROUND

1. Field of the Invention

The present invention generally relates to stent coatings that includebioactive compounds that inhibit restenosis.

2. Description of the Related Art

Stents are often used in the treatment of atherosclerosis, a disease ofthe vascular system in which arteries become partially, and sometimescompletely, occluded with substances that may include lipids,cholesterol, calcium, and various types of cells, such as smooth musclecells and platelets. Atherosclerosis is a very common disease that canbe fatal, and methods of preventing the accumulation of occludingcompounds in arteries are being investigated.

Percutaneous transluminal angioplasty (PTA) is a commonly used procedureto break up and/or remove already formed deposits along arterial walls.PTA can also be used to treat vascular occlusions not associated withatherosclerosis. During PTA, a catheter is threaded through a patient'sarteries until the occluded area to be treated is reached. A balloonattached to the end of the catheter is then inflated at the occludedsite. The expanded balloon breaks up the mass of occluding substances,resulting in a more open arterial lumen. However, there is a risk thatthe artery may re-close within a period of from one day to approximatelysix months of the procedure. This re-closure is known as restenosis.Accordingly, a balloon-only angioplasty procedure often does not resultin a permanently reopened artery. To prevent restenosis, scaffoldingdevices called stents are deployed in the lumen of the artery as astructural support to maintain the lumen in an open state. Unlike theballoon and the catheter used in an angioplasty procedure, the stentusually remains in the artery as a permanent prosthesis. Althoughtechnically feasible, removal of the stent from the artery is generallyavoided.

Stents are typically elongated structures used to keep open lumens(e.g., openings in the body) found in various parts of the body so thatthe parts of the body containing those lumens may function properly.Stents are usually implanted at their site of use in the body byattaching them in a compressed state to a catheter that is directedthrough the body to the site of stent use. The stent can be expanded toa size which enables it to keep the lumen open by supporting the wallsof the lumen once it is positioned at the desired site.

The lumens of blood vessels are common sites of stent deployment.Vascular stents are frequently used in blood vessels to open the vesseland provide improved blood flow. The stents are typically hollow,cylindrical structures made from struts or interconnected filaments.Vascular stents can be collapsed to reduce their diameter so that thestent can be guided through a patient's arteries or veins to reach thesite of deployment. Stents are typically either coupled to the outsideof the balloon for expansion by the expanding balloon or areself-expanding upon removal of a restraint such as a wire or sleevemaintaining the stent in its collapsed state.

The stent is allowed to expand at the desired site to a diameter largeenough to keep the blood vessel open. Vascular stents are often made ofmetal to provide the strength necessary to support the occluded arterialwalls. Two of the preferred metals are Nitinol alloys of nickel andtitanium, and stainless steel. Other materials that can be used infabricating stents are ceramics, polymers, and plastics. Stents may becoated with a substance, such as a biodegradable or biostable polymer,to improve the biocompatibility of the stent, making it less likely tocause an allergic or other immunological response in a patient. Acoating substance may also add to the strength of the stent. Some knowncoating substances include organic acids, their derivatives, andsynthetic polymers that are either biodegradable or biostable. Biostablecoating substances do not degrade in the body, biodegradable coatingsubstances can degrade in the body. A problem with known biodegradableand biostable stent coatings is that both types of coatings aresusceptible to breaking and cracking during the temperature changes andexpansion/contraction cycles experienced during stent formation and use.

Stents located within any lumen in the body may not always preventpartial or complete restenosis. In particular, stents do not alwaysprevent the re-narrowing of an artery following PTA. In fact, theintroduction and presence of the stent itself in the artery or vein cancreate regions of trauma such as, e.g., tears in the inner lining of theartery, called the endothelium. It is believed that such trauma cantrigger migration of vascular smooth muscle cells, which are usuallyseparated from the arterial lumen by the endothelium, into the arteriallumen, where they proliferate to create a mass of cells that may, in amatter of days or weeks, occlude the artery. Such re-occlusion, which issometimes seen after PTA, is an example of restenosis. Coating a stentwith a substance to make the surface of the stent smoother and tominimize damage to the endothelium has been one method used to createstents that are less likely to contribute to restenosis.

Currently, drug therapy for restenosis primarily consists of thesystemic administration of drugs. However, delivering drugs in thismanner may result in undesirable side effects in other areas of the bodyunrelated to the vascular occlusion. Also, the administered dose of adrug that is delivered systemically is less effective in achieving thedesired effect in the local area of the body in which it is needed. Forexample, an anti-restenosis drug delivered systemically may besequestered or metabolized by other parts of the body, resulting in onlya small amount of the drug reaching the local area in which it isneeded.

Stents with bioactive compounds or drugs in or on their coatings can beused. One class of drugs that can be used in stent coatings isrestenosis inhibitors. There remains a need for coatings that can beshown to actually release the restenosis inhibiting compounds in theiractive forms. Further, there is a need for stents that can carry drugsand release them in a sufficient concentration to produce the desiredeffect. In particular, there is a need for such stents that can inhibitrestenosis.

SUMMARY OF INVENTION

Broadly, the invention relates to coated stents, methods of makingcoated stents and methods of using coated stents. In one aspect, theinvention can include a coated stent comprising a stent and a coatingcomprising a substantially unreacted HMG-CoA reductase inhibitor. It ispreferred that the coating also comprise a carrier for the HMG-CoAreductase inhibitor. In a specific embodiment, the HMG-CoA reductaseinhibitor is provided in a nonpolymeric carrier. In another embodiment,the HMG-CoA reductase inhibitor is provided in a polymeric carrier,which may be physically bound to the polymer, chemically bound to thepolymer, or both. The coating composition can be a liquid solution atroom and/or body temperature, which may include the HMG-CoA reductaseinhibitor and the polymeric or nonpolymeric carrier, and which mayadditionally include a solvent which later may be removed, e.g., bydrying. Alternatively, the coating composition may be a solid at roomand body temperature.

The coating composition preferably includes an effective amount of theHMG-CoA reductase inhibitor. More particularly, the coating compositionpreferably includes an amount of the HMG-CoA reductase inhibitor that issufficient to be therapeutically effective for inhibiting regrowth ofplaque or inhibiting restenosis. In one embodiment, the coatingcomposition may include from about 1 wt % to about 50 wt % HMG-CoAreductase inhibitor, based on the total weight of the coatingcomposition. In another embodiment, the coating composition includesfrom about 5 wt % to about 30 wt % HMG-CoA reductase inhibitor. In yetanother embodiment, the coating composition includes from about 10 wt %to about 20 wt % HMG-CoA reductase inhibitor. Any HMG-CoA reductaseinhibitor may be used, but the HMG-CoA reductase inhibitor is preferablyselected from the group consisting of cerivastatin, atorvastatin,simvastatin, fluvastatin, lovastatin, and pravastatin. More preferably,the HMG-CoA reductase inhibitor is cerivastatin. In another embodiment,the coating composition comprises more than one HMG-CoA reductaseinhibitor. In another embodiment, the coating composition includes arestenosis inhibitor that is not an HMG-CoA reductase inhibitor.

In one embodiment, the coating composition comprises an effective amountof a polymeric carrier, e.g., an amount sufficient to provide a polymermatrix or support for the inhibitor. The polymer is preferablynon-reactive with the HMG-CoA reductase inhibitor, i.e., no chemicalreaction occurs when the two are mixed. The polymer may be a polymerhaving no functional groups. Alternatively, the polymer may be onehaving functional groups, but none that are reactive with the HMG-CoAreductase inhibitor. The polymer may include a biodegradable polymer.For example, the polymer may include a polymer selected from the groupconsisting of polyhydroxy acids, polyanhydrides, polyphosphazenes,polyalkylene oxalates, biodegradable polyamides, polyorthoesters,polyphosphoesters, polyorthocarbonates, and blends or copolymersthereof. The polymer may also include a biostable polymer, alone or incombination with a biodegradable polymer. For example, the polymer mayinclude a polymer selected from the group consisting of polyurethanes,silicones, polyacrylates, polyesters, polyalkylene oxides, polyalcohols,polyolefins, polyvinyl chlorides, cellulose and its derivatives,fluorinated polymers, biostable polyamides, and blends or copolymersthereof.

In another embodiment, the coating composition comprises an effectiveamount of a non-polymeric carrier. In a particular embodiment, thenon-polymeric carrier comprises a fatty acid. The non-polymeric carriermay alternatively comprise a biocompatible oil, wax, or gel. In a yetfurther embodiment, the non-polymeric carrier may comprise a mixture ofone or more of a fatty acid, an oil, a wax, and/or a gel.

In another aspect, the invention can include a method of coating astent. In a specific embodiment, the method includes providing a coatingcomposition comprising a blend of a substantially unreacted HMG-CoAreductase inhibitor and a polymeric or nonpolymeric carrier, andapplying the coating composition to the stent. Providing the coatingcomposition may include mixing the I-IMG-CoA reductase inhibitor and anonpolymeric liquid carrier. In one embodiment, the nonpolymeric liquidcarrier comprises a C-6 to C-18 fatty acid. In another embodiment,providing the coating composition may include mixing the HMG-CoAreductase inhibitor and a polymeric liquid carrier. In a furtherembodiment, providing the coating composition may include mixing theHMG-CoA reductase inhibitor, a polymer, and a solvent under conditionssuch that the HMG-CoA reductase inhibitor does not chemically react withthe polymer, or does not react to any substantial extent. Providing thecoating composition may also include mixing the HMG-CoA reductaseinhibitor, a polymer, and a solvent at a temperature of from about 20°C. to about 30° C., preferably at about 25° C. The method of coating thecomposition may further comprise removing the solvent by, e.g., drying.In another embodiment, providing a coating composition may includeproviding a solid coating comprising an HMG-CoA reductase inhibitor anda polymer.

In another embodiment, a method of coating a stent may further compriseexpanding the stent to an expanded position before applying the coatingcomposition to the stent. The coating composition may be applied to thestent by any number of ways, e.g., by spraying the coating compositiononto the stent, by immersing the stent in the coating composition, or bypainting the stent with the coating composition. Other coating methods,such as electrodeposition can also be used. In one embodiment, excesscoating composition is allowed to drain from the stent. In anotherembodiment, the stent is dried after the coating composition is appliedto the stent to provide a solid coating composition. The coatingcomposition may be formed into a solid film that is then applied to thestent by wrapping the film around the stent.

In another aspect, the invention includes a method of treating anoccluded artery comprising providing a stent, providing a coatingcomposition comprising a nonpolymeric or polymeric carrier and a HMG-CoAreductase inhibitor in an amount effective to prevent or substantiallyreduce restenosis, applying the coating composition to the stent, anddeploying the stent in the occluded artery at the site of occlusion.Providing a coating composition may comprise dissolving or suspending anamount of the HMG-CoA reductase inhibitor effective to prevent orsubstantially reduce restenosis in a nonpolymeric carrier that is aliquid at room and/or body temperature. In another embodiment, providinga coating composition may comprise dissolving in a polymeric carrierthat is a liquid at room and/or body temperature an amount of theHMG-CoA reductase inhibitor effective to prevent or substantially reducerestenosis in an occluded vascular lumen. In alternative embodiments,the nonpolymeric or polymeric carrier may be a solid at room and bodytemperature. Where a polymeric carrier is provided, the HMG-CoAreductase inhibitor may be physically bound to the polymer, chemicallybound to the polymer, or both. The coating composition may be a solutionwhich includes the HMG-CoA reductase inhibitor, the polymer, and asolvent. The solvent may be removed by, e.g., drying the stent or othermethods known in the art to yield a stent having a solid polymericcarrier for the HMC-CoA reductase inhibitor. The coating composition mayinclude an amount of the HMG-CoA reductase inhibitor that istherapeutically effective for inhibiting regrowth of plaque orinhibiting restenosis. More particularly, the coating composition mayinclude from about 1 wt % to about 50 wt % HMG-CoA reductase inhibitor,based on the total weight of the coating composition.

In another aspect, the invention can include a method of treatingrestenosis, comprising inserting a coated stent into a body lumen, thecoated stent comprising a stent and a coating composition comprising asubstantially unreacted HMG-CoA reductase inhibitor and a nonpolymericor polymeric carrier, which may be a liquid at room and bodytemperature, a solid at room and body temperature, or a solid at roomtemperature and a liquid at body temperature. In one embodiment, thecoated stent releases the HMG-CoA reductase inhibitor in an amountsufficient to inhibit or reduce the regrowth of plaque. In anotherembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount sufficient to inhibit or reduce restenosis.

In another aspect, the invention can include a method of localizeddelivery of an HMG-CoA reductase inhibitor, comprising inserting acoated stent into a body lumen, the coated stent comprising a stent anda coating composition comprising a substantially unreacted HMG-CoAreductase inhibitor and a polymeric or nonpolymeric carrier. In oneembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount effective to inhibit the regrowth of plaque. In anotherembodiment, the coated stent releases the HMG-CoA reductase inhibitor inan amount effective to inhibit restenosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-section of an artery experiencing restenosis in thepresence of an uncoated stent.

FIG. 2 is a cross-section of an artery containing a coated stent.

FIG. 3 is a stent of a type suitable for use in connection with thepresent invention.

FIG. 4 is a UV-VIS spectra of cerivastatin released from a stentcoating.

FIG. 5 is a release profile of cerivastatin released from a stentcoating of EVA film.

FIG. 6 is a release profile of cerivastatin released from a stentcoating of polycaprolactone film.

FIG. 7 is a release profile of cerivastatin released from a stent coatedwith silicone.

FIG. 8 is a release profile of cerivastatin released from a stent coatedwith liquid vitamin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

An exemplary artery 10 experiencing restenosis is shown in FIG. 1. Theendothelium 12 normally serves as a solid barrier between the layer ofsmooth muscle cells 14 and the arterial lumen 20. Small tears 16 in theendothelium 12 can expose smooth muscle cells 14, which can then migrateinto the arterial lumen 20 and hyperproliferate into a mass 18 which canpartially or completely occlude the lumen 20 even though an uncoatedstent 21 is placed, during a procedure such as angioplasty, in theartery 10 to keep the arterial lumen 20 open.

An artery 10 containing a coated stent 22 prepared according to anembodiment herein is shown in FIG. 2. The stent has a coating 24containing a polymer and a bioactive compound that inhibits restenosis.By using a stent having this coating 24, the tears 16 shown in FIG. 1 inthe endothelium 12 may be reduced or eliminated. Additionally, the mass18 created by a proliferation of smooth muscle cells 14, as shown inFIG. 1, is eliminated or substantially reduced.

FIG. 3 illustrates a stent 21 suitable for use in connection with thepresent invention. In one embodiment, the stent 21 comprises a hollowreticulated tube. The tubular body of stent 21 is defined by a number offilaments or struts 25 which surround open cells 26. The stent 21comprises an inner surface 27 facing the interior of the stent and anouter surface 28 facing the exterior. In a preferred embodiment, acoating (now shown) covers both the inner surface 27 and the outersurface 28. In alternative embodiments, the coating may cover only theinner surface, only the outer surface, or portions of one or both of theinner and outer surfaces. The coating may aggregate at the intersectionof filaments. In a preferred embodiment, the coated stent 22 (FIG. 2) ismade out of a metal or metal alloy, such as titanium, tantalum,stainless steel, or nitinol. In a preferred embodiment, the coating 24is made by mixing together an HMG-CoA reductase inhibitor, and a carrierin which both the HMG-CoA reductase inhibitor is soluble. In aparticularly preferred embodiment, the carrier is a liquid oil thatadheres to the inner and outer surfaces 27, 28 of the stent 22. In otherembodiments, the carrier comprises a polymer dissolved in a solvent,which is then removed, e.g., by drying, to yield a solid coatingcomposition comprising the polymer and the HMG-CoA reductase inhibitor.

As discussed, the coated stent of this invention includes a stent and acoating composition. The coating composition is preferably a blend ofHMG-CoA reductase inhibitor and a liquid oil capable of adhering to theinner surface 27 and/or the outer surface 28 of the stent 22. In anotherembodiment, the coating composition comprises a blend of HMG-CoAreductase inhibitor and a polymer. These two ingredients are preferablyblended, e.g., mixed thoroughly but not chemically reacted to anysubstantial degree. Preferably the HMG-CoA reductase inhibitor is“substantially unreacted.” The term “substantially unreacted,” whenreferring to the HMG-CoA reductase inhibitor, means that the inhibitordoes not chemically react with the oil, the polymer or any othercomponent of the coating or the stent, to any degree that substantiallyreduces its biological activity, such as inhibiting restenosis by, e.g.,inhibiting the proliferation of smooth muscle cells 14. Where thecoating comprises a polymer, the reductase inhibitor is physically boundto the polymer and/or to the stent, but is not chemically bound to anysignificant degree. In a preferred embodiment, the carrier, whetherliquid or solid, polymeric or nonpolymeric, is incapable of reactingchemically with the inhibitor, i.e., is totally non-reactive (inert)with respect to the inhibitor.

The HMG-CoA reductase inhibitor should remain active even after beingcoupled to the carrier to form the coating composition and even afterthe coating composition is applied to the stent and the device issterilized. Preferably, the reductase inhibitor remains active when thecoated stent is introduced into the body of a patient, e.g., through alumen, and is also still active when it is released from the stent. An“effective amount” of the HMG-CoA reductase inhibitor means an amountthat is sufficient, when delivered to a localized area in the body lumenof a patient, to inhibit the proliferation of smooth muscle cells in abody lumen of a patient. An “effective amount” of the carrier means anamount of carrier sufficient to provide an amount of the coatingcomposition to substantially coat the portion of the stent that isdesired to be coated, preferably the entire stent. Preferably, thecarrier has no functional groups that react with the HMG-CoA reductaseinhibitor under the conditions of forming the blend of the HMG-CoAreductase inhibitor and the carrier. The term “biodegradable” is appliedherein to any carrier, whether polymeric or nonpolymeric, and whetherliquid or solid, that breaks down in the body. The term “biostable” isapplied herein to any carrier, whether polymeric or nonpolymeric, andwhether liquid or solid, that does not break down in the body. The term“biocompatible” describes any material that is not harmful to and doesnot cause an immunological response in a body, e.g., a human being.

In accordance with methods and compositions described herein, restenosismay be prevented or lessened using localized delivery of HMG-CoAreductase inhibitors from a stent placed in a body lumen. Preferably,metal stents are coated with a biocompatible coating compositioncomprising a carrier containing an effective amount of an HMG-CoAreductase inhibitor. The coated stent can be deployed during anyconventional percutaneous transluminal angioplasty (PTA) procedure.Controlled delivery from a stent of the active HMG-CoA reductaseinhibitor, using a stent such as that described herein, in an effectiveamount, can inhibit the regrowth of plaque and prevent restenosis. Whilethe stents shown and described in the various embodiments are vascularstents, any type of stent suitable for deployment in a body lumen of apatient may be used with the coatings described herein.

An important aspect of this invention is the carrier used to form thecoating composition. The coating composition may comprise more than onecompound in a liquid carrier. The coating composition may alternativelycomprise more than one solid compound in a solid carrier. The coatingcomposition may further comprise both a liquid carrier and a solidcarrier. In a still further aspect, the coating composition may alsocomprise more than one type of nonpolymeric or polymeric compound in thecarrier, and may further comprise both a polymeric material and anonpolymeric material in a solid or liquid carrier. In a yet furtheraspect of the invention, the coating composition may comprise more thanone type of HMG-CoA reductase inhibitor. In coatings created by thismethod, the HMG-CoA reductase inhibitors are preferably physically boundto the carrier but not chemically bound thereto. Accordingly, thechemical or molecular structure of the HMG-CoA reductase inhibitor ispreferably unchanged when they are mixed with the polymers to form thecoating. Therefore, when the HMG-CoA reductase inhibitor is releasedfrom the coating, it remains in the desired active form.

In order to create coatings in which HMG-CoA reductase inhibitors arephysically rather than chemically bound to the polymers in the coatings,HMG-CoA reductase inhibitors and carriers are chosen such that they willnot have functional groups that will react with each other under thecompounding conditions of to form the coating solution.

The carriers in the coating composition may be either biodegradable orbiostable. Biodegradable polymers are often used in syntheticbiodegradable sutures. These polymers include polyhydroxy acids.Polyhydroxy acids suitable for use in the present invention includepoly-L-lactic acids, poly-DL-lactic acids, polyglycolic acids,polylactides including homopolymers and copolymers of lactide (includinglactides made from all stereo isomers of lactic acids, such as D-,L-lactic acid and meso lactic acid), polylactones, polycaprolactones,polyglycolides, polypara-dioxanone, poly 1,4-dioxepan-2-one, poly1,5-dioxepan-2-one, poly 6,6-dimethyl-1,4-dioxan-2-one,polyhydroxyvalerate, polyhydroxybuterate, polytrimethylene carbonatepolymers, and blends of the foregoing. Polylactones suitable for use inthe present invention include polycaprolactones such aspoly(e-caprolactone), polyvalerolactones such as poly(d-valerolactone),and polybutyrolactones. Other biodegradable polymers that can be usedare polyanhydrides, polyphosphazenes, biodegradable polyamides such assynthetic polypeptides such as polylysine and polyaspartic acid,polyalkylene oxalates, polyorthoesters, polyphosphoesters, andpolyorthocarbonates. Copolymers and blends of any of the listed polymersmay be used. Polymer names that are identical except for the presence orabsence of brackets represent the same polymers.

Biostable polymers that are preferred are biocompatible. Biostablepolymers suitable for use in the present invention include, but are notlimited to polyurethanes, silicones such as polyalkyl siloxanes such aspolydimethyl siloxane and copolymers, acrylates such as polymethylmethacrylate and polybutyl methacrylate, polyesters such aspoly(ethylene terephthalate), polyalkylene oxides such as polyethyleneoxide or polyethylene glycol, polyalcohols such as polyvinyl alcoholsand polyethylene glycols, polyolefins such as polyethylene,polypropylene, poly(ethylene-propylene) rubber and natural rubber,polyvinyl chloride, cellulose and modified cellulose derivatives such asrayon, rayon-triacetate, cellulose acetate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose etherssuch as carboxymethyl cellulose and hydroxyalkyl celluloses, fluorinatedpolymers such as polytetrafluoroethylene (Teflon), and biostablepolyamides such as Nylon 66 and polycaprolactam. Fixed animal tissuessuch as glutaraldehyde fixed bovine pericardium can also be used.Polyesters and polyamides can be either biodegradable or biostable.Ester and amide bonds are susceptible to hydrolysis, which cancontribute to biodegradation. However, access to water, and thus,hydrolysis, can be prevented by choosing certain neighboring chemicalstructures.

In a preferred embodiment, the polymer used to form the coatingcomposition is polycaprolactone. Polycaprolactone is biocompatible, andit has a low glass transition temperature, which gives it flexibly andallows it to withstand the temperature changes stents often experienceduring their formation and use. For example, nitinol stents arepreferably cooled to a temperature of about −50° C. so that they becomeflexible and can be compressed and fitted onto a catheter. A sheathplaced over the stent (or another restraint such as a wire binding theends of the stent), prevents the stent from expanding as it isintroduced into a patient's body at a higher temperature. The sheath orother restraint is removed at the site of the stent's use, and the stentre-expands to the size at which it is coated with a composition thatincludes polycaprolactone. Polycaprolactone, unlike some other stentcoating materials, does not become brittle and crack throughout thesefluctuations in stent temperature and size. Preferably, thepolycaprolactone has a molecular weight between about 20,000 and2,000,000, and provides a stronger and more uniform coating than lowermolecular weight polymers.

Generally, the HMG-CoA reductase inhibitor is released from the stent bydiffusion of the HMG-CoA reductase inhibitor out of the carrier. If thecarrier comprises a biodegradable polymer, the HMG-CoA reductaseinhibitor is preferably released from the stent by the degradation ofthe polymer. A controlled release of the HMG-CoA reductase inhibitorfrom the coating can be achieved with a carrier comprising both a liquidand a solid through the relatively rapid release of the diffusion of theHMG-CoA reductase inhibitor from the liquid and a slower release fromthe solid. In a still further embodiment, a highly controlled deliveryof the HMG-CoA reductase inhibitor can be achieved by a carriercomprising a liquid, a biodegradable (preferably solid) polymer, and abiostable (preferably solid) polymer. An initial release of the HMG-CoAreductase inhibitor from the liquid may be followed by a slower releasefrom the biodegradable solid, and a still slower release from thebiostable solid.

The diffusion rate of the HMG-CoA reductase inhibitor from the carriercan be determined by release studies and the dose of the HMG-CoAreductase inhibitor can be adjusted to deliver the drug at a desiredrate. In one embodiment, a higher dose of an HMG-CoA reductase inhibitorcan be delivered over a short period of time by using a liquid thatreleases a known amount of the inhibitor within one to three days. Inanother embodiment, a higher dose of an HMG-CoA reductase inhibitor canbe delivered over a short period of time by using a nonpolymeric liquidcarrier such as vitamin E. In another embodiment, the inhibitor can bedelivered via a biodegradable polymer that degrades within a few days,e.g., low molecular weight polyglycolic acid, releasing the HMG-CoAreductase inhibitor by both diffusion and/or coating degradation. Inanother embodiment, a biodegradable polymer which delivers an HMG-CoAreductase inhibitor primarily through diffusion is used. An example ofsuch a polymer is polycaprolactone, which degrades after several yearsin the body.

Advantageously, the rate of release of a HMG-CoA reductase inhibitorfrom a coating can be more easily predicted and is more consistent thanthe rate of release of a drug from other coatings in which the drug ischemically bound to the coating. With the coatings described herein, theHMG-CoA reductase inhibitors are preferably physically released from thecoatings, and thus, not dependent on a chemical step, such ashydrolysis, whose rate could vary in different patients as well aswithin the same patient.

The coating composition comprising the carrier and the HMG-CoA reductaseinhibitor can be applied to a stent in a number of different ways.Preferably, a stent is coated in its expanded form so that a sufficientamount of coating will be applied to coat the expanded stent. In apreferred embodiment, the coating composition is at least initiallyapplied to the stent as a liquid. Where the coating compositioncomprises a solid polymer, the polymer is preferably dissolved in asuitable solvent to form a polymer solution and the stent is sprayedwith the solution in order to coat the stent struts. Alternatively, thepolymer solution may be painted on the stent or applied by other meansknown in the art, such as electrodeposition, dipping, casting ormolding. The solvent may then be dried to yield a solid coatingcomposition comprising the polymer. In a preferred embodiment, the stentis dried at from 20° C. to 30° C. or ambient temperature for a period oftime sufficient to remove the solvent. The drying temperature should notbe high as to cause the polymer to react chemically with the HMG-CoAreductase inhibitor.

Multiple layers of the polymer solution may be applied to the stent.Preferably, each layer is allowed to dry before the next coating isapplied. While an HMG-CoA reductase inhibitor is included in at leastone layer of the coating, the coating solution in a second coating orother layers may optionally also contain the same or a different HMG-CoAreductase inhibitor. The polymer solution for each layer may contain thesame or different polymers. The number of layers and the polymers in thelayers can be chosen to deliver an HMG-CoA reductase inhibitor in acontrolled manner because the rate of diffusion of the HMG-CoA reductaseinhibitor through a known thickness of polymers can be estimated ormeasured directly.

In one embodiment, a first layer of the polymer solution, e.g., a primerlayer, may be applied to improve the adhesion of the coating compositionto the stent surface. Generally, coating a stent by completelyencapsulating the struts of the stent is preferred. Completeencapsulation typically provides uniform distribution of a drug alongthe surfaces of the stent. A completely encapsulated coated stent isalso more resistant than a partially coated stent to peeling and othermechanical stresses encountered during stent deployment. In certainspecific embodiments, a top layer of the polymer solution without a drugmay be applied on the coating. The top coating may be used to controlthe diffusion of the drug from the stent. The thickness of the coatingis preferably 0.1 microns to 2 mm. More preferably, the thickness of thecoating is from 1 to 50 microns. Most preferably, the thickness of thecoating is from 10 to 30 microns. Accordingly, specific embodiments ofthe invention include a stent with multiple coatings or layers, e.g.,films. For example, a stent with three or more coatings or layers can beprovided, where the first layer (contacting the stent) comprises a firstcarrier material having substantially no HMG-CoA reductase inhibitor,the second layer (applied to the outer surface of the first layer)includes the HMG-CoA reductase inhibitor in a second carrier material,and the third layer (applied to the second layer) comprises a thirdcarrier material having substantially no HMG-CoA reductase inhibitor.

In another embodiment, the polymer solution can be formed into a filmand the film then applied to the stent. Any of a variety of conventionalmethods of forming films can be used. For example, the polymer, HMG-CoAreductase inhibitor and solvent are preferably mixed into solution andthen poured onto a smooth, flat surface such that a coating film isformed after the solution is dried to remove the solvent. The film canthen be cut to fit the stent on which it is to be used. The film maythen be mounted, such as by wrapping, on the outer surface of a stent.

As used herein, the term “solvent” is defined according to its broadestrecognized definition and includes any material into which the polymerand the HMG-CoA reductase inhibitor can dissolve, fully or partially, atroom temperature or from 20° C. to 40° C. Methylene chloride is apreferred solvent. Methylene chloride's low boiling point facilitatesremoval from the polymer and the HMG-CoA reductase inhibitor at ambienttemperatures by evaporation. However, it is contemplated that virtuallyany organic solvent that dissolves the polymer can be used. Solventsthat can cause corrosion, such as highly acidic or basic aqueoussolutions, are not preferred. Organic solvents that are biocompatible,have low boiling points and high flash points, are preferred. Othersolvents that may be used include chloroform, toluene, cyclohexane,acetone, methylethyl ketone, ethyl formate, ethyl acetate, acetonitrile,n-methylpyrrolidinone, dimethyl sulfoxide, n,n-dimethylacetamide,n,n-dimethyl formamide, ethanol, methanol, acetic acid, andsupercritical carbon dioxide.

In a particularly preferred embodiment, the coating compositioncomprises a nonpolymeric liquid that remains a liquid after it isapplied to the stent and the stent is deployed within the body of apatient, i.e., the coating liquid has a melting point below bodytemperature (37° C.), preferably below 30° C., more preferably belowroom temperature (22° C.), more preferably below 20° C., still morepreferably below 10° C. The liquid is preferably a viscous liquid thatadheres to at least a portion of the external surface 28 of the stent 22in sufficient quantity to deliver a therapeutically effective amount ofthe HMG-CoA reductase inhibitor upon expansion in the body of thepatient. Although the viscous liquid may be hydrophilic, in a preferredembodiment the viscous liquid is hydrophobic. Specifically, the carriermay comprise liquid Vitamin E.

In another preferred embodiment, the viscous, hydrophobic liquidcomprises a C4-C36 fatty acid or mixtures of such fatty acids, such asoleic acid or stearic acid, by way of nonlimiting example. In yetanother preferred embodiment, the viscous, hydrophobic liquid comprisesan oil. Exemplary oils suitable for use in the present invention includepeanut oil, cottonseed oil, mineral oil, low molecular weight (C4-C36),and other viscous organic compounds that behave as oils such as, by wayof nonlimiting example, 1,2 octanediol and other low molecular weightalcohols and polyols. Spraying the stent with the liquid carrier resultsin a coating of uniform thickness on the struts of the stent. In anotherembodiment, the stent may be dip coated or immersed in the solution,such that the solution completely coats the struts of the stent.Alternatively, the stent may be painted with the solution, such as witha paint brush. In each of these coating applications, the entirety ofboth the outer and inner surfaces of the stent are preferably coated,although only portions of either or both surfaces may be coated in someembodiments.

In yet a further embodiment of the present invention the coatingcomposition comprises a nonpolymeric compound that is a solid at roomtemperature but becomes a liquid at or near body temperature. Inparticular, the coating composition comprises low molecular weight waxesand derivatives having a melting point at between about 30° C. and 40°C., more particularly from about 35° C. to 40° C. and more particularlyabout 36° C. to about 38° C. In preferred embodiments, the low meltingsolid is applied to the stent by heating the solid to above its meltingpoint, then sprayed, painted, dipped, molded, or otherwise applied tothe stent as a liquid and allowing the liquid to resolidify uponcooling. The stent may then be deployed in the body lumen, whereupon thecoating composition re-liquifies.

In a preferred embodiment, the HMG-CoA reductase inhibitor used in thecoating composition is cerivastatin. Cerivastatin is a very potentHMG-CoA reductase inhibitor. For example, when it is administeredsystemically, a therapeutic dose of cerivastatin is less than 1 mg perday, while other HMG-CoA reductase inhibitors must be administered in 50mg doses. A thinner stent coating can be used if cerivastatin is thechosen HMG-CoA reductase inhibitor instead of other HMG-CoA reductaseinhibitors because less coating is needed. For example, a stent coatingpreferably has a thickness of about 10-100 μm. If less drug and lesscoating to carry the drug are required, a stent coating having apreferable thickness of 10-25 μm can be used. A thinner stent coatingmay be preferred because it leaves more of the arterial lumen open forblood flow. Thinner coatings are also useful in preserving sidebranchaccess. Sidebranches are small blood vessels that branch out from thecorollary artery and provide blood to some part of the heart.

Cerivastatin has other properties, in addition to its ability to inhibitthe proliferation of smooth muscle cells that can contribute torestenosis, making it a desirable component of stent coatings. Forexample, cerivastatin has anti-thrombotic activity. Stents can often besites of thrombus formation in the body because of theimmunologically-triggered aggregation of different cell types and bloodcomponents at the site of a foreign object in the body. Thus, includingcerivastatin in a stent coating may help prevent thrombus formation atthe site of the stent. Cerivastatin also promotes endothelialization, orthe repair of the endothelium 12 after it is damaged, such as by thedelivery and expansion of the stent in an artery or other body lumen. Itis contemplated that the endothelialization triggered by cerivastatincan help repair the endothelium, and thus reduce tears in theendothelium through which smooth muscle cells and other cell types canmigrate into the arterial lumen and proliferate, leading to restenosis.

Other HMG-CoA reductase inhibitors may be used in these stent coatings.For example, atorvastatin, simvastatin, fluvastatin, lovastatin, andpravastatin may be used. While these compounds are known for theirantihypercholesterolemic properties, it is believed that they may haveother beneficial activities, such as restenosis inhibition or inhibitionof cell proliferation, when they are delivered in a localized manner,such as from a stent coating.

In one embodiment, the coating compositions described herein may includemore than one type of HMG-CoA reductase inhibitor. For example, acoating composition may include cerivastatin and lovastatin. In otherspecific embodiments, the stent coatings described herein may includeone or more drugs or bioactive compounds that inhibit restenosis and arenot HMG-CoA reductase inhibitors. These drugs include, but are notlimited to, rapamycin, paclitaxel, actinomycin D, nicotine, andbioactive derivatives, analogues, and truncates of the foregoing. It iscontemplated that combining these drugs with an HMG-CoA reductaseinhibitor will provide a more effective coating composition forinhibiting restenosis than a coating composition containing only onerestenosis inhibiting agent. However, the foregoing may also be usedwithout an HMG-CoA reductase inhibitor.

EXAMPLES

The following examples are included to demonstrate differentillustrative embodiments or versions of the invention. However, thoseskilled in the art will, in light of the present disclosure, appreciatethat many changes can be made in the specific embodiments which aredisclosed and still obtain a like or similar result without departingfrom the spirit and scope of the invention.

Coronary stents were provided by Baylor Medical School and SulzerIntratherapeutics. Poly(lactic acid)-co-poly(glycolic acid) (PLGA)polymer was purchased from Boehringer Ingelheim. Methylene chloride waspurchased from Aldrich. Poly(ethylene-co-vinyl acetate) (EVA) copolymerwas purchased from Aldrich or Polymer Sciences. Sulzer Carbomedics, Inc.provides medical grade silicone rubber.

Example 1

One hundred (100) mg PCL (poly caprolactone) polymer and 10 mg ofcerivastatin were dissolved in 10 ml methylene chloride solution at roomtemperature. The solution was poured onto a glass plate and the solventwas allowed to evaporate for 12-24 hours. After almost complete removalof the solvent, the cerivastatin-loaded PCL film was removed from theglass plate and was cut to 1.5 cm by 1.5 cm size. The film was mountedon a Palmaz-Schatz coronary endovascular stent. Control PCL films wereprepared in the following manner: 100 mg PCL (poly caprolactone) polymerwas dissolved in 10 ml methylene chloride solution at room temperature.The solution was poured onto a glass plate and the solvent was allowedto evaporate for 12-24 hours. After almost complete removal of thesolvent, the control PCL film was removed from the glass plate and wascut to 1.5 cm by 1.5 cm size. The control film was mounted on aPalmaz-Schatz coronary endovascular stent. Release profiles wereobtained for the coated stents as shown in FIG. 6.

Example 2

100 mg EVA (ethylene-vinyl acetate) polymer and 10 mg of cerivastatinwere dissolved in 10 ml methylene chloride solution at room temperature.The solution was poured onto a glass plate and the solvent was allowedto evaporate for 12-24 hours. After almost complete removal of thesolvent, the cerivastatin-loaded EVA film was removed from the glassplate and was cut to 1.5 cm by 1.5 cm size. The film was mounted on aPalmaz-Schatz coronary endovascular stent. Control EVA films wereprepared in the following manner: 100 mg EVA (ethylene-vinyl acetate)polymer was dissolved in 10 ml methylene chloride solution at roomtemperature. The solution was poured onto a glass plate and the solventwas allowed to evaporate for 12-24 hours. After almost complete removalof the solvent, the control EVA film was removed from the glass plateand was cut to 1.5 cm by 1.5 cm size. The control film was mounted on aPalmaz-Schatz coronary endovascular stent. Release profiles wereobtained for the coated stents as shown in FIG. 5.

Example 3

A 0.6% solution of polycaprolactone dissolved in methylene chloride wasprepared at room temperature. The solution was sprayed onto a SulzerIntratherapeutics nitinol Protege model endovascular stent (6 mm×20 mm)using a semi-automated nebulizer apparatus. The nebulizer spray systemprovided a means of rotating and traversing the length of the stent at acontrolled rate. The traversing component of the apparatus contained aglass nebulizer system that applied nebulized polycaprolactone solutionto the stent at a rate of 3 ml per minute. Once applied, the 10 mgpolymer coating was “reflowed” by application of 60° C. heated air forapproximately 5 seconds. The process of reflowing the polymer providesbetter adherence to the stent surface. A drug-loaded polymer coating canbe provided using this technique by first preparing a 1%-20%cerivastatin/polymer solution in methylene chloride with subsequentapplication to the stent surface using the same nebulizer coatingsystem.

Example 4

A 1% solution of uncured two-part silicone rubber dissolved intrichloroethylene was applied to a “Protege” nitinol stent in the mannerdescribed in Example 3. The coated stent was dried at room temperaturefor 15 minutes to allow the trichloroethylene to evaporate. Once 10 mgof silicone was coated onto the stent, the composite device containingboth uncured polymer and nitinol was heated in a vacuum oven for aperiod of four hours in order to crosslink the silicone coating. Afterthe coated stents were removed from the oven and allowed to cool for aperiod of 1 hour, cerivastatin was loaded into the silicone coating bythe following method. Three mg of cerivastatin was dissolved in 300 μlof methylene chloride at room temperature. A volume of 100 μl ofmethylene chloride was applied to the silicone coating of each stent indropwise fashion. In this manner, each stent was loaded with 1 mgcerivastatin, for a final concentration of 10% w/w. The crosslinkedsilicone absorbed the drug/solvent solution, where the solventsubsequently evaporated at room temperature, leaving behind the drugentrapped within the silicone. By this method, a diffusion-based releasesystem for cerivastatin was created. A release profile was obtained forthe coated stent as shown in FIG. 7.

Example 5

A 10% w/w solution of cerivastatin in vitamin E was created by thefollowing method. Four mg of cerivastatin was dissolved in 100 μl ofmethylene chloride. This solution was added to 36 mg of liquid vitamin Eand mixed manually by stirrer. The solution was allowed to stand at roomtemperature for 1 hour to enable the methylene chloride to evaporatefrom the solution. The resulting cerivastatin/vitamin E mixture was usedto coat three Protege model stents by simple surface application.Approximately 10-12 mg of vitamin E and drug was deposited on eachstent. A release profile was obtained for the coated stent as shown inFIG. 8.

In preferred embodiments, the controlled release studies were done todetermine the integrity and activity of cerivastatin released fromstents coated with polymer and cerivastatin. Stents coated according tothe process of Example 2 were immersed in an Eppendorf tube containing 1ml phosphate buffered saline (PBS) and incubated on a rotator in a 37°C. oven. Buffer exchanges were performed at 1, 2, and 4 days followingimmersion in PBS. Collected samples were assayed for the spectralcharacteristics of cerivastatin using a UV-VIS spectrophotometer.Cerivastatin released from an EVA and cerivastatin coated stent such asthe stent of Example 2 and pure cerivastatin in deionized water hadalmost identical UV-VIS spectra, as shown in FIG. 4, suggesting that thecerivastatin released from the stent was unaltered and thus remainedbiologically active.

The release of cerivastatin from stents coated according to the processof Example 2 was monitored over 7 days, as shown in FIG. 5. An EVA andcerivastatin coated stent such as the stent of Example 2 released >20μg/ml cerivastatin per day, which is significantly higher than the 0.5μg/ml concentration needed to inhibit proliferation of smooth musclecells. Thus, stents produced according to this invention release asufficient amount of cerivastatin to inhibit the proliferation of smoothmuscle cells which occurs during restenosis.

The release of cerivastatin from stents coated with polycaprolactonefilm according to the process of Example 1 was monitored over 80 days,as shown in FIG. 6. A polycaprolactone and cerivastatin coated stentsuch as the stent of Example 1 released >20 μg/ml cerivastatin per day.The release of cerivastatin from stents according to the process ofExample 4 was monitored over 20 days, as shown in FIG. 7. A cerivastatinand silicone coated stent such as the stent of Example 4 released >20μg/ml cerivastatin per day.

The release of cerivastatin from stents according to the process ofExample 5 was monitored over 11 days, as shown in FIG. 8. A liquidvitamin E and cerivastatin coated stent such as the stents of Example 5released >20 μg/ml cerivastatin per day.

While the foregoing is directed to embodiments of the present invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof, and the scope thereof isdetermined by the claims that follow, including equivalents.

1. A coated stent comprising: a coating composition comprising anHMG-CoA reductase inhibitor in an effective amount, of about 1 to 50wt.-%, and a polymeric carrier component; wherein the polymeric carriercomponent comprises a polymer selected from polycaprolactone,ethylene-vinyl acetate polymer, and a two-part silicone rubber, whereinthe HMG-CoA reductase inhibitor is selected from the group consisting ofcerivastatin, fluvastatin, simvastatin, lovastatin, atorvastatin,pravastatin and mixtures thereof, and wherein the HMG-CoA reductaseinhibitor is released from the coated stent at a rate of >20 μg/ml perday.
 2. The coated stent of claim 1, further comprising a catheterwherein the catheter and the coated stent can be coupled to form atreatment assembly.
 3. The coated stent of claim 1 wherein the coatingcomposition comprises about equal parts by weight of the HMG-CoAreductase inhibitor and the first polymeric carrier component.
 4. Thecoated stent of claim 1 further comprises a rapamycin compound.
 5. Thecoated stent of claim 1 which further comprises one or more bioactivecompounds are selected from the group consisting of paclitaxel,actinomycin D, rapamycin, and mixtures thereof.
 6. The coated stent ofclaim 1 which further comprises one or more bioactive compounds areselected from the group consisting of analogs of paclitaxel, actinomycinD, rapamycin, and mixtures thereof.